Genetic analysis of phenylalanine hydroxylase (PAH) in psychiatric patients and control subjects has shown that a mutation in the cofactor binding domain of the PAH enzyme is identified in patients only among those with the diagnosis of schizophrenia (SZ). Although the study group was of mixed ethnicity, all subjects with this K274E mutation were of African- American ethnicity. Biochemical analyses suggest that the PAH gene K274E mutation has physiological consequences related to neurotransmitter function. PAH shares physical, structural and catalytic properties with tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH). The cofactor binding domain is highly conserved in all three members of the aromatic amino acid hydroxylase superfamily. TH catalyzes the rate-limiting step in the synthesis of catecholamines such as dopamine and noradrenaline, and TPH catalyzes the rate-limiting step in the biosynthesis of serotonin. Since these neurotransmitter systems have all been implicated in the pathophysiology os SZ, the aromatic amino acid hydroxylases are among the likely candidates for genes conferring SZ susceptibility. In this pilot study, genomic DNA from African-American SZ subjects and from genetically unrelated "never mentally ill" African-American controls in the NIMH Schizophrenia and Bipolar Disorder Genetics Initiative databases will be screened by DNA sequencing to identify genetic variants in the conserved cofactor binding region of PAH, TH and TPH. The discovery of genetic variants in this functionally critical region of the aromatic amino acid hydroxylases with greater frequency in subjects with SZ than in controls, would provide justification for a large scale study to confirm statistical association between hydroxylase genotype and psychiatric phenotype. The demonstration of such a statistical association could contribute to the development of diagnostic tests that could identify individuals at risk for developing the disorder, prior to manifestation of psychiatric symptoms. Among SZ patients, the mutations could identify subgroups whose illness share a common etiology. The functional correlates observed for the PAH K274E mutation indicate that other cofactor binding domain variants in SZ patients may similarly have biochemical and physiological consequences which would suggest possible mechanisms by which genetic variants may affect the pathophysiology of the disorder. Elucidation of mechanisms by which aromatic amino acid hydroxylase mutations may confer susceptibility to SZ, would be an important step in the development of appropriate treatments and/or preventive measures.